Abstract:
:Patient survival in pancreatic cancer remains poor with gemcitabine (GEM)-based regimens. The target specific molecular agent lapatinib, a dual ErbB1 and ErbB2 receptor tyrosine kinase inhibitor, has shown significant activity against ErbB1 and ErbB2-expressing tumors. Since pancreatic tumors frequently overexpress these proteins, we investigated its effects, both alone and in conjunction with 5-FU or GEM. The pancreatic cancer cell lines PANC-1 and AsPC were treated with varying doses of lapatinib in vitro. The effects on ErbB1/ErbB2 protein phosphorylation and on the cell survival protein survivin were determined by western blotting. Cytotoxicity was determined by MTT assay and apoptosis was measured using the caspase-3 colorimetric assay. Similar dose-response lapatinib experiments were conducted with varying concentrations of 5-FU or GEM and isobolograms were constructed to evaluate therapeutic synergy. Lapatinib inhibited protein phosphorylation in the range of 4-16 µM, a clinically achievable concentration. The lapatinib-treated cells showed a dose-dependent inhibition of cell proliferation and induction of apoptosis at the same concentrations that blocked ErbB1/ErbB2 phosphorylation. The addition of 5-FU or GEM to these cells resulted in synergistic effects. The lapatinib-treated cells also demonstrated downregulation of survivin. Simultaneous dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition with lapatinib results in significant reduction of pancreatic cancer cell growth and proliferation. These effects occur at clinically achievable concentrations and are synergistic with the effects of 5-FU or GEM. These findings support the potential role of lapatinib in the treatment of pancreatic cancer.
journal_name
Oncol Repjournal_title
Oncology reportsauthors
Singla S,Pippin JA,Drebin JAdoi
10.3892/or.2012.2053subject
Has Abstractpub_date
2012-12-01 00:00:00pages
2211-6issue
6eissn
1021-335Xissn
1791-2431journal_volume
28pub_type
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